In recent years, coronary cardio-circulary diseases, e.g., atherosclerosis and hypercholesterolemia, have increasingly become a major cause of deaths. It has been reported that an elevated plasma cholesterol level causes the deposition of fat, macrophages and foam cells on the wall of blood vessels, such deposit leading to plaque formation and then to atherosclerosis (Ross, R., Nature, 362, 801-809(1993)). One of the methods for decreasing the plasma cholesterol level is alimentotherapy to reduce the ingestion of cholesterol and lipids. Another method is to inhibit the absorption of cholesterol by inhibiting enzymes involved therein.
Acyl CoA-cholesterol-o-acyltransferase (ACAT) promotes the esterification of cholesterol in blood. Foam cells are formed by the action of ACAT and contain a large amount of cholesterol ester carried by low density lipoproteins. The formation of foam cells on the wall of artery increases with the ACAT activity, and, accordingly, an inhibitor of ACAT may also be an agent for preventing atherosclerosis. Further, it has been reported that the blood level of LDL-cholesterol can be reduced by inhibiting the ACAT activity (Witiak, D. T. and D. R. Feller (eds.), Anti-Lipidemic Drugs: Medicinal, Chemical and Biochemical Aspects, Elsevier, pp159-195(1991)).
On the other hand, deterioration of hepatic functions may occur due to an excessive intake of alcohol or foods having a high lipid content, or an infection of hepatitis B or C virus, and it may develop into hepatitis, hepatocirrhosis or hepatic cancer. In particular, the excessive intake of fat-containing foods and alcohol causes fatty liver wherein a large amount of lipids is deposited in the liver tissue and the levels of serum GOT (glutamate-oxaloacetate transaminase), GPT (glutamate-pyruvate transaminase) and .gamma.-GTP (.gamma.-glutamyl transpeptidase) are elevated (T. Banciu et al., Med. Interne., 20, 69-71(1982); and A. Par et al., Acta. Med. Acad. Sci. Hung., 33, 309-319(1976)).
Numerous efforts have been made to develop medicines which inhibit ACAT activity; and, as a result, several compounds isolated from the cultures of various microorganisms have been reported. Examples of such compounds include pyripyropenes isolated from the culture of Aspergillus fumigatus (S. Omura et al., J. Antibiotics, 46, 1168-1169(1993)) and Acaterin isolated from Pseudomonas sp. (S. Nagamura et al., J. Antibiotics, 45, 1216-1221(1992)).
Further, as a treating agent for hypercholesterolemia, a HMG-CoA reductase inhibitor named Lovastatin.RTM. has been developed and marketed by Merck Co., U.S.A. However, this medicine is known to induce adverse side effect of increasing creatin kinase in the liver.
Accordingly, there has continued to exist a need to develop non-toxic inhibitors of ACAT and macrophage-lipid complex accumulation on the arterial epithelium, and a preventive or treating agent for the hepatic diseases.
The present inventors have endeavored to develop a novel and potent ACAT inhibitor, macrophage-lipid complex accumulation inhibitor and treating agent for the hepatic diseases from natural materials, and, as a result, have discovered that naringin or naringenin has a potent ACAT inhibitory activity, macrophage-lipid complex accumulation inhibitory activity, and preventive or treating activity on the hepatic diseases.
Naringin (C.sub.27 H.sub.32 O.sub.14, M.W.: 580.53) and the aglycon of naringin, naringenin (C.sub.15 H.sub.12 O.sub.5, M.W.: 272.25), are flavonoids found in lemons, grapefruits, tangerines, citrons and oranges (Citrus sinensis) (Horowitz, Gentili, Tetrahedron, 19, 773(1963)).
It has been reported that naringin or naringenin has anti-cancer, anti-viral and cholesterol lowering activities (Monforte, M. T., et al., Farmaco., 50(9), 595-599(September 1995); JP 95-86929; JP 95-86930; Felica, V., et al., J. Med. Virol., 15, 71-79(1985); EP 0352147 A2(1990.1.24); and Martin, M. J., et al., Pharmacol., 49, 144-150(1994)).
Further, naringin has been used as a bitter tasting agent, sweetener or chewing gum base.
However, hitherto, none of the ACAT inhibitory activity, macrophage-lipid complex accumulation inhibitory activity and preventive or treating activity on the hepatic diseases of naringin or naringenin has been reported.